Rifaximin is a semi-synthetic, non-systemic antibiotic that can be derived from rifamycin O by condensation with 2-amino-4-methylpyridine. Xifaxan® has Rifaximin as the active ingredient, and its labels are hereby incorporated by reference.
The U.S. Pat. No. 4,341,785, U.S. Pat. No. 4,557,866, U.S. Pat. No. 7,045,620, U.S. Pat. No. 7,612,199, U.S. Pat. No. 7,902,206, U.S. Pat. No. 7,906,542, U.S. Pat. No. 7,928,115, U.S. Pat. No. 7,915,275, U.S. Pat. No. 7,923,553, U.S. Pat. No. 8,158,644, U.S. Pat. No. 8,158,781, and U.S. Pat. No. 8,193,196 provide methods for the synthesis of polymorphic forms of rifaximin and are hereby incorporated by reference in their entireties.
The U.S. Pat. No. 4,341,785 describes the preparation and use of new imidazo-rifamycin derivatives of a general formula which includes the antibiotic rifaximin, having the structure
among the compounds claimed therein.
In U.S. Pat. No. 4,557,866, a process is described for conversion of rifamycin O to rifaximin by contacting rifamycin O with 2-amino-4-methylpyridine. The product was purified by crystallization from ethanol/water 7:3.
The U.S. Pat. No. 7,045,620 describes crystalline polymorphous forms of rifaximin, named rifaximin α and rifaximin β, and a poorly crystalline form named rifaximin γ. These forms were described as obtained by means of a crystallization process carried out by hot-dissolving the raw rifaximin in ethyl alcohol and by causing the crystallization of the product by the addition of water at a determinate temperature and for a determinate period of time. The crystallization was followed by drying carried out under controlled conditions until a specific water content was reached in the end product. The rifaximin α and rifaximin β crystalline polymorphs were characterized by X-ray diffractogram properties. It is described that the production of rifaximin α and rifaximin β during drying depends on the amount of water remaining at the end, higher or lower than 4.5%, and not from the experimental conditions of pressure and temperature at which this critical limit of water percentage is achieved. In fact, the two polymorphous forms, with higher or lower water content, can be obtained by drying under vacuum or at atmospheric pressure, at room temperature or at high temperatures, in the presence or in the absence of drying agents, provided that the drying is conducted for the amount of time necessary so that the water percent characteristic for each polymorphous form is achieved. It is described in the U.S. Pat. No. 7,045,620 that polymorphous form rifaximin β is obtained when the drying of the product, crystallized and washed with water, is stopped at values of water higher than 4.5% and that the polymorphous form rifaximin α is obtained by continuing the drying until values lower than 4.5%, preferably between 2.0% and 3.0%, are reached. The polymorphous form rifaximin α, kept in an ambient environment with a relative humidity higher than 50% for a period of time between 12 and 48 hours, turns into the polymorphous form β, which in turn, by drying until an amount of water lower than 4.5% is reached, preferably comprised between 2.0% and 3.0%, turns back into the polymorphous form rifaximin α.
In U.S. Pat. No. 7,612,199, it is disclosed that the polymorph called rifaximin α is characterized by a water content lower than 4.5%, preferably between 2.0% and 3.0% and from a powder X-ray diffractogram which shows peaks at the values of the diffraction angles 2θ of 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11.1°; 11.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; 22.1°. The polymorph called rifaximin β is characterized by a water content higher than 4.5%, preferably between 5.0% and 6.0%, and by a powder X-ray diffractogram which shows peaks at the values of the diffraction angles 2θ of 5.4°; 6.4°; 7.0°; 7.8°; 9.0°; 10.4°; 13.1°; 14.4°; 17.1°; 17.90; 18.30; 20.9° The polymorph called rifaximin γ is characterized by a powder X-ray diffractogram much poorer because of the poor crystallinity; the significant peaks are at the values of the diffraction angles 2θ of 5.0°; 7.1°; and 8.4°.
Crystal forms of rifaximin and their effect on pharmaceutical properties, are further described in Viscomi G C, et al, The Royal Society of Chemistry, CrystEngComm, 2008, 10, 1074-1081, which is hereby incorporated by reference in its entirety.
U.S. Pat. No. 8,158,781 and U.S. Pat. No. 8,158,644 claim the individual α, β, and γ crystalline polymorphs of rifaximin.